Aminoaryl oxazolidinone N-oxides

ABSTRACT

The present invention provides for aminoaryl oxazolidinone N-oxide compounds of Formula I  
                 
 
     wherein the variables are as defined herein. These compounds are exceedingly water soluble which is useful in preparing pharmaceutical formulations of these compounds. They are also rapidly converted back to the parent amines in vivo, making them useful as prodrugs of the parent amines. They are effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant  staphylococci, streptococci  and  enterococci  as well as anaerobic organisms, such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as  Mycobacterium tuberculosis, Mycobacterium avium  and Mycobacterium spp., and in organisms such as Mycoplasma spp.

[0001] This application claims the benefit of provisional applicationU.S. Ser. No. 60/003,838, filed Sep. 15, 1995, under 35 USC 119(e)(i).

FIELD OF THE INVENTION

[0002] The present invention provides for aminoaryl oxazolidinoneN-oxide compounds. These compounds are exceedingly water soluble whichis useful in preparing pharmaceutical formulations of these compounds.They are also rapidly converted back to the parent amines in vivo,making them useful as prodrugs of the parent amines.

[0003] These compounds have antibiotic activity comparable to the parentamines. They are effective against a number of human and veterinarypathogens, including gram-positive aerobic bacteria such asmultiply-resistant staphylococci, streptococci and enterococci as wellas anaerobic organisms, such as Bacteroides spp. and Clostridia spp.species, and acid-fast organisms such as Mycobacterium tuberculosis,Mycobacterium avium and Mycobacterium spp., and in organisms such asMycoplasma spp.

BACKGROUND OF THE INVENTION

[0004] A variety of antibiotic oxazolidinone compounds are known in theart. For example, please see the following:

[0005] WO 95/07271, published Mar. 16, 1995, “Substituted Oxazine andThiazine Oxazolidinones Antimicrobials”; WO96/15130, published May 23,1996, “Bicyclic Oxazine and Thiazine Oxazolidinone Antibacterials”;WO96/13502, published May 9, 1996, “Phenyloxazolidinone Antimicrobials”;WO 93/23384, published Nov. 25, 1993, “Oxazolidinone AntimicrobialsContaining Substituted Diazine Moieties”; WO 90/02744, published Mar.22, 1990; U.S. Pat. Nos. 5,164,510; 5,225,565; 5,182,403;“5′-Indolinyl-5 β-Amidomethyloxazolidin-2-ones”; WO 95/25106, publishedSep. 21, 1995, “Oxazolidinone Derivatives and PharmaceuticalCompositions Containing Them”; WO 93/09103, published May 13, 1993,“Substituted Aryl and Heteroaryl-Phenyloxazolidinones”; WO 95/14684,published Jun. 1, 1995, “Esters of Substituted Hydroxyacetyl-PiperazinePhenyl Oxazolidinones”; PCT/US96/05202, filed Apr. 18, 1996,“Spirocyclic and Bicyclic Diazinyl and Carbazinyl Oxazolidinones”; U.S.Pat. Nos. 5,231,188 and 5,247,090, “Tricyclic [6,6,5]-FusedOxazolidinone Antibacterial Agents;” WO 96/23788, published Aug. 8,1996, “Hetero-Aromatic Ring Substituted PhenyloxazolidinoneAntimicrobials;” and WO 94/13649, published Jun. 23, 1994,“Tropone-Substituted Phenyloxazolidinone Antibacterial Agents.”

[0006] Nowhere do these patents, applications or publications teach orsuggest N-oxide oxazolidinone compounds.

Information Disclosure

[0007] U.S. Pat. No. 4,722,928 discloses N-oxide prodrug derivatives of3-hydroxy morphinans and partial morphinans analgesics,agonist-antagonists, and narcotic antagonists, which are usefultherapeutic entities providing enhanced bioavailability of thesecompounds from orally administered dosage forms. In contrast, there isno change in the bioavailability of the N-oxide compounds of the presentinvention.

[0008] This patent further states that there is no way to accuratelypredict which prodrug structure will be suitable for a particular drug.A derivative which may work well for one drug may not do so for another.Differences in the absorption, metabolism, distribution, and excretionamong drugs do not permit generalizations to be made about prodrugdesign.

[0009] Chemical Abstracts 118:1⁴7331y (1993) discloses anti-canceranthracene amine N-oxide prodrugs with low cytotoxicity which arebioreduced within anaerobic neoplastic tissue to the cytotoxic amineanticancer agents. There is no suggestion that N-oxide prodrugs can bebioreduced in normal tissue. These compounds are also potentially usefulagainst anaerobic bacterial and protozoal infections.

[0010] L. H. Patterson, “Rationale for the use of aliphatic N-oxides ofcytotoxic anthraquinones as prodrug DNA binding agents: a new class ofbioreductive agent,” Cancer and Metastasis Review 12:119-134 (1993)discloses that such N-oxides are not intrinsically cytotoxic. It furtherstates that investigations into the fate of N-oxide administration toanimals show that, in general, aliphatic N-oxides are stable in vivo andare recovered quantitatively following intravenous dosing. Hence, thearticle concludes that it would appear that aliphatic N-oxides are notmetabolised in oxygenated tissue to any significant extent. In contrast,the aliphatic N-oxide compounds of the present invention aresurprisingly and unexpectedly reduced back to the parent amine veryrapidly in vivo.

[0011] The problem in the art is difficulty in formulating the parentamine compounds for intravenous and injectable use. The N-oxidecompounds of the present invention have high water solubility and arereadily formulated in aqueous vehicles.

SUMMARY OF THE INVENTION

[0012] The present invention particularly provides:

[0013] A compound of the formula I

[0014] wherein X¹ and X² are independently

[0015] —H,

[0016] —F, or

[0017] —Cl;

[0018] wherein Q¹ is:

[0019] wherein Z¹ is

[0020] a) —CH₂—, or

[0021] b) —CH(R⁵)—CH₂—;

[0022] wherein Z² is

[0023] a) —O₂S—,

[0024] b) —O—, or

[0025] c) —N(R⁸);

[0026] wherein Z³ is

[0027] a) —O₂S—, or

[0028] b) —O—;

[0029] wherein A¹ is

[0030] a) H—, or

[0031] b) CH₃—;

[0032] wherein A² is

[0033] a) H—,

[0034] b) HO—,

[0035] c) CH₃CO₂—,

[0036] d) CH₃—,

[0037] e) CH₃O—,

[0038] f) R²O—CH₂—C(O)—NH—

[0039] g) R³—C(O)—NH—,

[0040] h) R⁴—C(O)—NH—,

[0041] i) (C₁-C₂)alkyl-O—C(O)—, or

[0042] j) HO—CH₂—; or

[0043] A¹ and A² taken together are:

[0044] a)

[0045] or

[0046] b) O═

[0047] wherein R¹ is

[0048] a) —CHO,

[0049] b) —COCH₃,

[0050] c) —COCHCl₂,

[0051] d) —COCHF₂,

[0052] e) —CO₂CH₃,

[0053] f) —SO₂CH₃, or

[0054] g) —COCH₂OH;

[0055] wherein R² is

[0056] a) H—,

[0057] b) CH₃—,

[0058] c) phenyl-CH₂—, or

[0059] d) CH₃C(O)—;

[0060] wherein R³ is

[0061] a) (C₁-C₃)alkyl-, or

[0062] b) phenyl-;

[0063] wherein R⁴ is

[0064] a) H—,

[0065] b) (C₁-C₄)alkyl,

[0066] c) aryl-(CH₂)_(p),

[0067] d) ClH₂C—,

[0068] e) Cl₂HC—,

[0069] f) FH₂C—,

[0070] g) F₂HC—, or

[0071] h) (C₃-C₆)cycloalkyl;

[0072] wherein R⁵ is

[0073] a) H—, or

[0074] b) (C₁-C₃)alkyl;

[0075] wherein R⁶ is

[0076] a) H—, or

[0077] b) HOH₂C—;

[0078] wherein R⁷ is

[0079] a) H—, or

[0080] b) H₃C—;

[0081] wherein R⁸ is

[0082] a) R²O—C(R₁₀)(R₁₁)—C(O)—,

[0083] b) R³O—C(O)—,

[0084] c) R⁴—C(O)—,

[0085] f) H₃C—C(O)—(CH₂)₂—C(O)—,

[0086] g) R⁹—SO₂—,

[0087] h)

[0088] i) R¹²—NH—C(O)—;

[0089] wherein R⁹ is

[0090] a) —CH₃,

[0091] b) —CH₂Cl

[0092] c) —CH₂CH═CH₂,

[0093] d) aryl, or

[0094] e) —CH₂CN;

[0095] wherein R¹⁰ and R¹¹ are independently

[0096] a) H—,

[0097] b) CH₃—; or

[0098] R¹⁰ and R¹¹ taken together are —CH₂—CH₂—;

[0099] wherein R¹² is —(CH₂)_(p)-aryl;

[0100] wherein R¹³ is

[0101] a) R²O—C(R₁₀)(R₁₁)—C(O)—,

[0102] b) R³O—C(O)—,

[0103] c) R⁴—C(O)—,

[0104] d) R⁹—SO₂—, or

[0105] e) R¹²—NH—C(O)—;

[0106] wherein m is zero (0) or one (1);

[0107] wherein n is one (1) to three (3), inclusive;

[0108] wherein p is zero (0) or one (1);

[0109] wherein aryl is phenyl substituted with zero (0) or one (1) ofthe following:

[0110] a)—F,

[0111] b) —Cl,

[0112] c) —OCH₃,

[0113] d) —OH,

[0114] e) —NH₂,

[0115] f) —(C₁-C₄)alkyl,

[0116] g) —O—C(O)—OCH₃,

[0117] h) —NO₂, or

[0118] i) —CN;

[0119] with the following provisos:

[0120] 1) in the moiety of formula II, Z¹ is —CH(R⁵)—CH₂— wherein R⁵ is(C₁-C₃)alkyl, only when n is one (1), A¹ is H and A² isR²O—CH₂—C(O)—NH—, R³O—C(O)—NH—, or R⁴—C(O)—NH—; and

[0121] 2) in the moiety of formula II, when Z¹ is —CH₂—, n is one (1).

[0122] The present invention more particularly provides:

[0123] The compound of claim 1 wherein Q¹ is the moiety of formula II;

[0124] The compound of claim 1 wherein Q is the moiety of formula m;

[0125] The compound of claim 1 wherein Q¹ is the moiety of formula IV;

[0126] The compound of claim 1 wherein Q is the moiety of formula V;

[0127] The compound of claim 1 wherein one of X¹ and X² is —H and theother is —F or wherein X¹ is —F and X² is —F; and

[0128] The compound of claim 1 wherein R¹ is acetyl.

[0129] The compounds of the present invention are named according to theIUPAC or CAS nomenclature system.

[0130] The carbon atom content of various hydrocarbon-containingmoieties is indicated by a prefix designating the minimum and maximumnumber of carbon atoms in the moiety, i.e., the prefix C_(i)-C_(j)indicates a moiety of the integer “i” to the integer “j” carbon atoms,inclusive. Thus, for example, (C₁-C₃)alkyl refers to alkyl of one tothree carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl,straight and branched forms thereof.

[0131] Throughout this application, abbreviations which are well knownto one of ordinary skill in the art may be used, such as “Ph” forphenyl, “Me” for methyl, and “Et” for ethyl.

[0132] The following Charts I-IX describe the preparation of the parentamine compounds, which are the starting compounds from which the N-oxidecompounds of the present invention are prepared. All of the startingcompounds are prepared by procedures described in these charts or byprocedures analogous thereto, which would be well known to one ofordinary skill in organic chemistry. The following applications andpublications which further describe and exemplify these procedures arehereby incorporated by reference herein: WO 95/07271, published Mar. 16,1995; WO96/15130, published May 23, 1996; WO 95/25106, published Sep 21,1995; WO96/13502, published May 9, 1996; WO 93/23384, published Nov. 25,1993; WO 95/4684, published Jun. 1, 1995; and PCTIUS96/05202, filed Apr.18, 1996.

[0133] In the text below corresponding to these charts, the formula atthe left margin corresponds to a specific Q² moiety in the charts andthe other variables are as defined with X¹ and X² most often beinghydrogen or fluorine and R¹ most often being —COCH₃, for purposes ofexample only.

Chart I

[0134] I-A Using the procedures from WO 95/07271, published Mar. 16,1995, page 21, line 33, thru page 23, line 32 for preparation of theintermediate sulfide and then oxidation to the sulfone using the generalprocedures from WO 95/07271, published Mar. 16, 1995, page 15, line 32thru page 16, line 14.

[0135] I-B Using the procedures described in WO 95/07271, published Mar.16, 1995, page 21, line 33, thru page 23, line 32, but substitutingoxazolidine for thiazolidine.

Chart II

[0136] II-A Using the general procedures from WO 95/07271, publishedMar. 16, 1995, page 12, line 31, thru page 16, line 14.

[0137] II-B Using the general procedures from WO 95/07271, publishedMar. 16, 1995, page 12, line 31 thru page 16, line 14, but substituting2-methylthiomorpholine for thiomorpholine. 2-Methylthiomorpholine isprepared according to the procedure of Gallego, et al, J. Org. Chem.,1993, 58, 3905-11.

[0138] II-C Using the general procedures from WO96/15130, published May23, 1996, Examples 2 and 3 at page 14, line 24, thru page 17, line 21.

Chart III

[0139] III-A Using the general procedures from WO 95/07271, publishedMar. 16, 1995, page 19, line 6, thru page 21, line 13; and page 23, line33, thru page 24, line 35.

[0140] III-B Using the general procedures from WO96/15130, published May23, 1996, Example 1 at page 12, line 1, thru page 14, line 22.

Chart IV

[0141] IV-A Using the general procedures from WO 95/25106, publishedSep. 21, 1995, page 20, line 27 thru page 22, line 5 but substitutingazetidine for piperidine.

[0142] IV-B Using the general procedures of WO96/13502, published May 9,1996, Example 11 at page 53, line 32 through page 56, line 3, butsubstituting 1-(diphenylmethyl)-3-azetidinone in place of1-benzyl-3-pyrrolidinone. 1-(Diphenylmethyl)-3-azetidinone can beprepared by the procedure of Chatterjee, et al, Synthesis, 1973, 153-4.

[0143] IV-C From IV-B using the general procedure from WO96/13502,published May 9, 1996, page 56, line 4 through line 17.

[0144] IV-D From IV-C using the general procedure from WO 95/25106,published Sep. 21, 1995, page 28, line 26 through page 29, line 5.

[0145] IV-E Using the general procedures from WO96/13502, published May9, 1996, Example 2 at page 33, line 4, thru page 36, line 22.

[0146] IV-F Starting with IV-E, and using procedures well known foracetylation; e.g., acetic anhydride and triethylamine in a suitablesolvent.

[0147] IV-G Using the general procedures from WO96/13502, published May9, 1996, Example 7 at page 43, line 36, thru page 47, line 28.

[0148] IV-H Using the general procedures from WO96/13502, published May9, 1996, Example 6 at page 40, line 31, thru page 43, line 34.

[0149] IV-I Using the procedures of WO96/13502, published May 9, 1996,Example 1 at page 29, line 25 thru page 33, line 2.

[0150] IV-J Wherein R² is H; using the procedure described inWO96/13502, published May 9, 1996, Examples 12 and 13 at page 56, line19 thru page 59, line 4, but substituting 3-acetylaminoazetidinehydrochloride in place of 3-(trifluoroacetylamino)pyrrolidinehydrochloride. 3-Acetylaminoazetidine hydrochloride is prepared by theprocedure of Nisato, et al., J. Heterocycl. Chem. 1985, 22, 961-3.

[0151] IV-J Wherein R² is methyl; using the procedure described inWO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidinehydrochloride in place of 3-(trifluoroacetylamino)pyrrolidinehydrochloride and substituting methoxyacetyl chloride in place ofbenzyloxyacetyl chloride.

[0152] IV-J Wherein R² is benzyl; using the procedure described inWO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidinehydrochloride in place of 3-(trifluoroacetylamino)pyrrolidinehydrochloride.

[0153] IV-J Wherein R² is acetyl; using the procedure described inWO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidinehydrochloride in place of 3-(trifluoroacetylamino)pyrrolidinehydrochloride and substituting acetoxyacetyl chloride in place ofbenzyloxyacetyl chloride.

[0154] IV-K Wherein R³ is methyl, ethyl, propyl, or phenyl; using theprocedure described in WO96/13502, published May 9, 1996, Examples 12,13 and 14 at page 56 line 19 thru page 59 line 27, but substituting3-acetylaminoazetidine hydrochloride in place of3-(trifluoroacetylamino)pyrrolidine hydrochloride and substitutingmethyl, ethyl, propyl, or phenyl chloroformate in place ofbenzyloxyacetyl chloride.

[0155] IV-L Wherein R⁴ is hydrogen; using the procedure described inWO96/13502, published May 9, 1996, Examples 12, 13 and 14 at page 56line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidinehydrochloride in place of 3-(trifluoroacetylamino)pyrrolidinehydrochloride and substituting methyl formate in place ofbenzyloxyacetyl chloride.

[0156] IV-L Wherein R⁴ is all others listed; using the proceduredescribed in WO96/13502, published May 9, 1996, Examples 12, 13 and 14at page 56 line 19 thru page 59 line 27, but substituting3-acetylaminoazetidine hydrochloride in place of3-(trifluoroacetylamino)pyrrolidine hydrochloride and substituting theappropriate acid chloride in place of benzyloxyacetyl chloride.

[0157] IV-M Using the general procedures of WO96/13502, published May 9,1996, Example 1, Steps 2 thru 7, at page 30, line 14 thru page 33, line2, but substituting methyl N-benzylazetidine-3-carboxylate in place of1-(diphenyl-methyl)-3-methoxyazetidine. MethylN-benzylazetidine-3-carboxylate can be prepared by the procedure ofMason, et al, EP 169602 A1.

[0158] IV-N Starting with IV-M and using the general procedures of WO95/25106, published Sep. 21, 1995, page 22, line 11 through line 20.

Chart V

[0159] V-A Using the procedure from WO 95/25106, published Sep. 21,1995, page 20, Example 1, but using-pyrrolidine instead of piperidine.

[0160] V-B Using the procedures of WO96/13502, published May 9, 1996,Example 11 at page 53, line 32, thru page 56, line 3.

[0161] V-C From V-B, following the procedure of WO96/13502, publishedMay 9, 1996, page 56, lines 4 through 17.

[0162] V-D From V-C, using the general procedure of WO 95/25106,published Sep. 21, 1995, page 28, line 26, thru page 29, line 5.

[0163] V-E Using the procedures described in WO96/13502, published May9, 1996, Example 10 at page 50, line 25, thru page 53, line 30. Or, fromV-C by reduction using methods well known in the art such as sodiumborohydride in methanol.

[0164] V-F From V-E using standard acetylation procedures; e.g., aceticanhydride in pyridine.

[0165] V-G As described in WO96/13502, published May 9, 1996, Example 7at page 43, line 36, thru page 47, line 28 but substituting1-benzyl-3-methyl-3-pyrrolidinol hydrochloride for1-(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride.1-Benzyl-3-methyl-3-pyrrolidinol hydrochloride can be prepared from1-benzyl-3-pyrrolidinone by methods known in the art, eg, reaction withmethylmagnesium bromide and treatment of the product with one equivalentof hydrochloric acid. 1-Benzyl-3-pyrrolidinone is commerciallyavailable.

[0166] V-H Using the general procedures of WO96/13502, published May 9,1996, Example 6 at page 40, line 31 through page 43, line 34, butsubstituting 1-benzyl-3-methyl-3-pyrrolidinol hydrochloride (prepared asdescribed above) in place of 1-(diphenylmethyl)-3-methyl-3-azetidinolhydrochloride.

[0167] V-I As described in WO96/13502, published May 9, 1996, Example 1at page 29, line 25, thru page 33, line 2, but substituting commerciallyavailable 1-benzyl-3-pyrrolidinol for 1-(diphenylmethyl)-3-azetidinol.

[0168] V-J Wherein R² is H and R⁵ is H; using the procedure described inWO96/13502, published May 9, 1996, Examples 12 and 13 at page 56, line19, thru page 59, line 4;

[0169] V-J Wherein R² is methyl and R⁵ is H; using the proceduredescribed in WO96/13502, published May 9, 1996, Example 12 at page 56,line 19 thru page 58, line 27 but substituting methoxyacetyl chloridefor benzyloxyacetyl chloride.

[0170] V-J Wherein R² is benzyl and R⁵ is H; using the proceduredescribed in WO96/13502, published May 9, 1996, Example 12 at page 56,line 19 thru page 58, line 27.

[0171] V-J Wherein R² is acetyl and R⁵ is H; using the proceduredescribed in WO96/13502, published May 9, 1996 , Example 12 at page 56,line 19 thru page 58, line 27 but substituting acetoxyacetyl chloridefor benzyloxyacetyl chloride.

[0172] V-J Where R² is H and R⁵ is methyl; using the proceduresdescribed in WO96/13502, published May 9, 1996 , Example 15 at page 62,lines 5-28.

[0173] V-J Wherein R² is benzyl and R⁵ is methyl; using the proceduresdescribed in WO96/13502, published May 9, 1996 , Example 15, Step 1, atpage 62, lines 5-19.

[0174] V-J Wherein R² is methyl or acetyl and R⁵ is methyl; using theprocedures described in WO96/13502, published May 9, 1996 , Example 15,Step 1, at page 62, lines 5-19, but substituting methoxyacetyl chlorideor acetoxyacetyl chloride for benzyloxyacetyl chloride.

[0175] V-J Wherein R⁵ is other alkyl; using the general proceduresdescribed above but subsituting other 4-alkyl-3-aminopyrrolidines inplace of 3-amino-4-methylpyrrolidine.

[0176] V-K Wherein R³ is methyl, ethyl, propyl or phenyl and R⁵ is H;using the procedure described in WO96/13502, published May 9, 1996 ,Example 12 at page 56, line 19 thru page 58, line 27 but substitutingmethyl chloroformate, ethyl choroformate, propylchloroformate, orphenylchloroformate for benzyloxyacetyl chloride.

[0177] V-K Wherein R³ is methyl, ethyl, propyl, or phenyl and R⁵ ismethyl; by reaction of(S)-(N)-[[[3-fluoro-4-(3-amino-4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamidewith the appropriate chloroformate. The above amine is preparedaccording to the procedures of WO96/13502, published May 9, 1996 ,Example 14, Steps 1-8, at page 59, line 6 through page 61, line 29.

[0178] V-K Wherein R⁵ is other alkyl; From the appropriate amine andchloroformate. The amine is prepared according to the procedures ofWO96/13502, published May 9, 1996 , Example 14, Steps 1-8, at page 59,line 6 through page 61, line 29, but starting with other3-alkyl-4-aminopyrrolidines in place of 4-amino-3-methylpyrrolidine.

[0179] V-L Where R⁴ is H and R⁵ is H; using the procedure described inWO96/13502, published May 9, 1996 , Example 12 at page 56, line 19 thrupage 58, line 27 but substituting methyl formate in place ofbenzyloxyacetyl chloride.

[0180] V-L Where R⁴ is all others listed and R⁵ is H; using theprocedure described in WO96/13502, published May 9, 1996 , Example 12 atpage 56, line 19 thru page 58, line 27 but substituting the appropriateacid chloride in place of benzyloxyacetyl chloride.

[0181] V-L Where R⁴ is H and R⁵ is methyl; by reaction of formic acidand dicyclohexylcarbodiimide. The required amine is prepared accordingto the procedures of WO96/13502, published May 9, 1996 , Example 14,Steps 1-8, at page 59, line 6 through page 61, line 29.

[0182] V-L Where R⁴ is all others and R⁵ is methyl; by reaction of(S)—(N)-[[[3-fluoro-4-(3-amino-4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamidewith the appropriate acid chloride. The required amine is preparedaccording to the procedures of WO96/13502, published May 9, 1996 ,Example 14, Steps 1-8, at page 59, line 6 through page 61, line 29.

[0183] V-L Where R⁵ is other alkyl; Using the above procedures, butstarting with other 3-alkyl-4-aminopyrrolidines in place of4-amino-3-methylpyrrolidine.

[0184] V-M Using the general procedure from WO 95/25106, published Sep.21, 1995, page 22, lines 6 through 12, 5, but usingpyrrolidine-3-carboxylic acid methyl ester instead ofpiperidine-4-carboxylic acid ethyl ester. Pyrrolidine-3-carboxylic acidmethyl ester is prepared by the procedure of Morgans, et al, TetrahedronLett., 1979, 1959.

[0185] V-N From V-M, using the general procedure of WO 95/25106,published Sep. 21, 1995, page 22, lines 12 through 20.

Chart VI

[0186] VI-A Using the general procedures from WO 95/25106, publishedSep. 21, 1995, page 20, line 27, thru page 22, line 5.

[0187] VI-B Using the procedure of WO 95/25106, published Sep. 21, 1995,WO 95/25106, published Sep. 21, 1995, page 22, line 21 thru line 26.

[0188] VI-C From VI-B, using the procedure from WO 95/25106, publishedSep. 21, 1995, page 22, lines 27 through 35.

[0189] VI-D From VI-C, using the procedure from WO 95/25106, publishedSep. 21, 1995, page 28, line 26 thru page 29, line 5.

[0190] VI-E Prepared from VI-C by reduction via standard proceduresknown in the art; eg, sodium borohydride in methanol.

[0191] VI-F Prepared from VI-E by procedures known in the art; eg,acetic anhydride and triethylamine.

[0192] VI-G Using the procedures from WO96113502, published May 9, 1996, Example 7, page 43, line 36 thru page 47, line 28 but substitutingcommercially available 4-hydroxy-4-methylpiperidine for3-hydroxy-3-methylazetidine.

[0193] VI-H Using the procedures from WO 95/25106, published Sep. 21,1995, page 20, line 27 thru page 22, line 5, but substituting4-methoxy-4-methylpiperidine in place of piperidine.4-Methoxy-4-methylpiperidine can be prepared according to the procedureof McManus, et al, J. Med. Chem., 1965, 8, 766-776.

[0194] VI-I Using the procedures from WO 95/25106, published Sep. 21,1995, page 20 line 27 thru page 22, line 5, but substituting4-methoxypiperidine for piperidine. 4-Methoxypiperidine can be made bythe procedure of McManus, et al, J. Med. Chem., 1965, 8, 766-776.

[0195] VI-J Wherein R²═H; Prepared by reaction of(S)-N-[[3-[4-(4-aminopiperidinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(prepared according to the procedures of WO 95/25106, published Sep. 21,1995, page 22, line36 thru page 23, line 24) with acetoxyacetyl chlorideand triethylamine followed by hydrolysis of the acetoxy group withmethanolic potassium carbonate.

[0196] VI-J Wherein R²=methyl; prepared by reaction of the startingmaterial of VI-J (R²═H) with methoxyacetyl chloride and triethylamine.

[0197] VI-J Wherein R² is benzyl; prepared by reaction of the startingmaterial of VI-J (R²═H) with benzyloxyacetyl chloride and triethylamine.

[0198] VI-J Wherein R² is acetyl; prepared by reaction of the startingmaterial of VI-J (R²═H) with acetoxyacetyl chloride and triethylamine.

[0199] VI-K Wherein R³ is methyl, ethyl, propyl, or phenyl; prepared byreaction of the starting material of VI-J (R²═H) with methyl-, ethyl-,propyl-, or phenylchloroformate.

[0200] VI-L Wherein R⁴═H; By reaction of the starting material of VI-J(R²═H) with methylformate.

[0201] VI-L Wherein R⁴=all others listed; By reaction of the startingmaterial of VI-J (R²═H) with the appropriate acid chloride.

[0202] VI-M Using the procedure from WO 95/25106, published Sep. 21,1995, page 22, line 6 thru line 12.

[0203] VI-N Using the procedure from WO 95/25106, published Sep. 21,1995, page 22, lines 12 through 20.

Chart VII

[0204] VII-A Using the general procedures of WO 95/25106, published Sep.21, 1995, page 20, line 27 through page 22, line 5, but substitutingcommercially available azepine in place of piperidine.

[0205] VII-B Using the procedure of WO 95/25106, published Sep. 21,1995, page 22, line 21 thru line 26 but substituting1,4-dioxo-8-aza-spiro[4.6]undecane for 1,4-dioxo-8-aza-spiro[4.5]decane.1,4-Dioxo-8-aza-spiro[4.6]undecane can be prepared by the procedure ofR. A. Johnson, et al, J. Org. Chem., 1968, 33, 3187-3195.

[0206] VII-C From VII-B, following the procedure of WO96/13502,published May 9, 1996, page 56, lines 4 through 17.

[0207] VII-D From VII-C using the general procedure of WO 95/25106,published Sep. 21, 1995, page 28, line 26, thru page 29, line 5.

[0208] VII-E Prepared from VII-C by reduction via standard proceduresknown in the art; eg, sodium borohydride in methanol.

[0209] VII-F Prepared from VII-E by procedures known in the art; eg,acetic anhydride and triethylamine.

[0210] VII-G Using the procedures from WO 96/13502, published May 9,1996 , Example 7, page 43, line 36 thru page 47, line 28 butsubstituting 4-hydroxy-4-methylazepine for 3-hydroxy-3-methylazetidine.4-Hydroxy-4-methylazepine can be prepared by the procedure pf Grob, etal, Helv. Chim.Acta, 1962, 45, 1823-1830.

[0211] VII-H Using the general procedures of WO96/13502, published May9, 1996 , Example 6, page 40, line 31 through page 43, line 34, butsubstituting 1-benzyl-4-methyl-4-azepinol in place of1-(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride.1-Benzyl-4-methyl-4-azepinol can be prepared by the reaction of methylmagnesium bromide with 1-benzyl-4-azepinone. 1-Benzyl-4-azepinone can beprepared by the procedure of Casy, et al. J. Chem. Soc. 1964, 5130-5132.

[0212] VII-I As described in WO96/13502, published May 9, 1996 , Example1, at page 29, line 25, thru page 33, line 2, but substituting1-benzyl-4-azepinol for 1-(diphenylmethyl)-3-azetidinol.1-Benzyl-4-azepinol can be prepared by the procedure of S. Sakanoue, etal, Chem. Pharm. Bull., 1990 38, 2981-2985.

[0213] VII-J Wherein R² is H; using the procedure described inWO96/13502, published May 9, 1996 , Examples 12 and 13, page 56, line19, thru page 59, line 4 but substituting4-(trifluoroacetylamino)azepine in place of3-(trifluoroacetylamino)pyrrolidine. 4-(Trifluoroacetylamino)azepine canbe prepared by reaction of 1-benzyl-4-azepinamine with trifluoroaceticanhydride in a suitable solvent such as chloroform, followed by removalof the benzyl protecting group via hydrogenolysis using palladium oncarbon as a catalyst in a solvent such as ethyl acetate.1-Benzyl-4-azepinamine can be prepared by the procedure of Morosawa, etal, Bull. Chem. Soc. Jpn., 1958, 31, 418-422.

[0214] VII-J Wherein R² is methyl; using the procedure described inWO96/13502, published May 9, 1996 , Example 12, page 56, line 19 throughpage 58, line 27, but substituting 4-(trifluoroacetylamino)azepine for4-(trifluoroacetylamino)pyrrolidine and substituting methoxyacetylchloride in place of benzyloxyacetyl chloride.

[0215] VII-J Wherein R² is benzyl; using the procedure described inWO96/13502, published May 9, 1996 , Example 12, page 56, line 19 throughpage 58, line 27, but substituting 4-(trifluoroacetylamino)azepine for4-(trifluoroacetylamino)pyrrolidine.

[0216] VII-J Wherein R² is acetyl; using the procedure described inWO96/13502, published May 9, 1996 , Example 12, page 56, line 19 throughpage 58, line 27, but substituting 4-(trifluoroacetylamino)azepine for4-(trifluoroacetylamino)pyrrolidine and substituting acetoxyacetylchloride in place of benzyloxyacetyl chloride.

[0217] VII-K Wherein R³ is methyl, ethyl, propyl, or phenyl; prepared byreaction of(S)—N-[[3-[4-(4-aminoazepinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyllmethyl]-acetamide (prepared as an intermediate in the synthesis ofVII-J) with the appropriate chloroformate and triethylamine inchloroform.

[0218] VII-L Wherein R⁴ is H; Prepared by reaction of(S)-N-[[3-[4-(4-aminoazepinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(prepared as an intermediate in the synthesis of VII-J) with formic acidaccording to the general procedure of WO 93/23384, published Nov. 25,1993, page 23, lines 4-17.

[0219] VII-L Wherein R⁴ is all others; Prepared by reaction of(S)-N-[[3-[4-(4-aminoazepinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(prepared as an intermediate in the synthesis of VII-J) with theappropriate acid chloride and triethylamine.

[0220] VII-M Using the procedure from WO 95/25106, published Sep. 21,1995, page 22, line 6 thru line 12, but substitutingazepine-4-carboxylic acid ethyl ester in place ofpiperidine-4-carboxylic acid ethyl ester. Azepine-4-carboxylic acidethyl ester can be prepared from azepine-4-carboxylic acid by normalprocedures known in the art, eg, reaction with ethanol and hydrochloricacid. Azepine-4-carboxylic acid can be prepared by the procedure ofKrogsgaard-Larsen, et al, Eur. J. Med. Chem. Chim. Ther., 1979, 14,157-164.

[0221] VII-N From VII-M, using the general procedure of WO 95/25106,published Sep. 21, 1995, page 22, lines 12 through 20.

Chart VIII

[0222] VII-A Wherein R²═H; According to the procedure of WO 95/14684,published Jun. 1, 1995, page 9, lines 1-28.

[0223] VIII-A Wherein R²=methyl; According to the general procedures ofWO 93/23384, published Nov. 25, 1993, page 19, lines 26-33.

[0224] VIII-A Wherein R²=benzyl; According to the procedure of WO95/14684, published Jun. 1, 1995, page 9, lines 1-14.

[0225] VIII-A Wherein R²=acetyl; According to the procedure of WO95/14684, published Jun. 1, 1995, page 28, lines 24-35.

[0226] VIII-B Wherein R³=Me, Et, Pr, or Ph; Using the general procedurefrom WO 93/23384, published Nov. 24, 1993, page 23, lines 19-28 andsubstituting methyl-, ethyl, propyl, or phenylchloroformate asappropriate.

[0227] VIII-C Wherein R⁴═H; Using the general procedures from WO93/23384, published Nov. 25, 1993, page 23, lines 4-17.

[0228] VIII-C Wherein R⁴=all others; Using the general procedures fromWO 93/23384, published Nov. 25, 1993, page 23, lines 19-28, andsubstituting the appropriate acid chloride for methylchloroformate.

[0229] VIII-D Prepared according to the general procedure found in WO93/23384, published Nov. 25, 1993, page 25, lines 13-25.

[0230] VII-E Prepared according to the general procedure from WO93/23384, published Nov. 25, 1993, page 25, lines 13-25, butsubstituting commercially available 5-oxo-2-tetrahydrofurancarboxylicacid in place of (R)-2-tetrahydrofuranoic acid.

[0231] VIII-F Prepared according to the procedure of WO 93/23384,published Nov. 25, 1993, page 18, lines 10-17.

[0232] VIII-G Prepared fromN-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamideand the appropriate sulfonyl chloride using the general procedure fromWO 93/23384, published Nov. 25, 1993, page 23, lines 19-28. Methyl,chloromethyl, allyl, and substituted arylsulfonyl chlorides arecommercially available. Cyanomethylsulfonyl chloride can be preparedaccording to the procedure of M. P. Sammes, et al, J. Chem. Soc. (C).,1971, 2151-2155.

[0233] VIII-H Prepared fromN-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamideand piperonyl chloride using the general procedure from WO 93/23384,published Nov. 25, 1993, page 23, lines 19-28. Piperonyl chloride iscommercially available.

[0234] VIII-I Prepared fromN-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamideand the appropriate carboxylic acid using the general procedure of WO95/14684, published Jun. 1, 1995, page 10, lines 4-17. The acids arecommercially available.

[0235] VIII-J Prepared fromN-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamideand the appropriate isocyanate. The required isocyanates arecommercially available.

Chart IX

[0236] IX-A Wherein R² is H; Prepared according to the procedures ofPCT/US96/05202, filed Apr. 18, 1996, Examples 1, 2 and 3, page 12, line11 through page 15, line 7.

[0237] IX-A Wherein R² is methyl; Prepared according to the generalprocedures of PCT/US96/05202, filed Apr. 18, 1996, Example 2, page 14,lines 16-32, but substituting methoxyacetyl chloride for benzyloxyacetylchloride.

[0238] IX-A Wherein R² is benzyl; Prepared accroding to the proceduresof PCT/US96/05202, filed Apr. 18, 1996. Example 2, page 14, lines 16-32.

[0239] IX-A Wherein R² is acetyl; Prepared according to the generalprocedures of PCT/US96/05202, filed Apr. 18, 1996, Example 2, page 14,lines 16-32, but substituting acetoxyacetyl chloride for benzyloxyacetylchloride. IX-B Using the general procedure of PCT/US96105202, filed Apr.18, 1996, Example 2, page 14, lines 16-32, but substituting theappropriate chloroformate for benzyloxyacetyl chloride.

[0240] IX-C Wherein R⁴ is H; Prepared from(S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]-octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(PCT/US96/05202, filed Apr. 18, 1996, page 14, lines 21-24) using thegeneral procedures from WO 93/23384, published Nov. 25, 1993, page 23,lines 4-16.

[0241] IX-C Wherein R⁴ is all others listed; Using the general procedureof PCT/US96/05202, filed Apr. 18, 1996, Example 2, page 14, lines 16-32,but substituting the appropriate acid chloride in place ofbenzyloxyacetyl chloride.

[0242] IX-D Using the general procedure of PCT/US96/05202, filed Apr.18, 1996, Example 2, page 14, lines 16-32, but substituting theappropriate sulfonyl chloride in place of benzyloxyacetyl chloride. Thesulfonyl chlorides can be obtained as described for VIII-G.

[0243] IX-E Prepared from(S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide (PCT/US96/05202, filed Apr. 18, 1996, page 14, lines21-24) and the appropriate carboxylic acid using the general proceduresof WO 93/23384, published Nov. 25, 1993, page 18, lines 10-17. Theappropriate carboxylic acids are commercially available.

[0244] IX-F Prepared by combining(S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(PCT/US96/05202, filed Apr. 18, 1996, page 14, lines 21-24) and theappropriate isocyanate. The required isocyanates are commerciallyavailable.

[0245] General Procedure:

[0246] The compounds of this invention are prepared by oxidation of asuitable precursor amine with any of a variety of oxidizing agents.Suitable oxidants include pertrifluoroacetic acid, meta-chloroperbenzoicacid (MCPBA), and magnesium monoperoxyphthalate (MMPP). For example, thesynthesis is shown below for the case wherein Q¹ is morpholine and theoxidant is MMPP.

[0247] Oxidation of any of the oxazolidinones of Charts I-IX in which Q²is any of the other groups previously described is carried outsimilarly.

[0248] Charts X-XVIII show the final N-oxide compounds of the presentinvention which are prepared from the parent amines of Charts I-IX,respectively, by using the above General Procedures.

[0249] It will be apparent to those skilled in the art that thedescribed synthetic procedures are merely representative in nature andthat alternative synthetic processes are known to one of ordinary skillin organic chemistry.

[0250] The compounds of the present invention have an advantage over theparent amines in being exceedingly water soluble (see Table 1 below).For example, the compound of Example No. 2 has a solubility of 409mg/ml. The parent amine has a water solubility of only 3.7 mg/ml. TheN-oxide compounds of the present invention also retain all the in vitroand in vivo activities of the parent amines. The enhanced watersolubility makes the N-oxide compounds of the present invention idealfor intravenous or injectable formulations TABLE 1 Solubility Data forthe N-oxides and parent amines. Parent Amine N-Oxide Solubility ExampleNumber Solubility (mg/mL) (mg/mL) 1 4.2 348 2 3.7 534 3 0.28 12.9 60.031 1.1

[0251] Procedure for Measuring Solubility:

[0252] In all solubility studies, an excess of compound is added to 0.5to 1 ml of pH 7, 50 mM phosphate buffer or other vehicle of interest.The samples are capped and stirred via magnetic stir bars for 24 to 48hours at room temperature. Samples are filter centrifuged (800×g) for5-10 minutes through Millipore Ultrafree-MC 0.22 micron filter units.The supernate is analyzed by either UV or HPLC to quantitate the drugconcentration. Results of the solubility testing of the compounds of thepresent invention are given above in Table 1.

[0253] The oxazolidinone compounds of the present invention have usefulactivity against a variety of microorganisms. The in vitro activity ofcompounds of the present invention are assessed by standard testingprocedures such as the determination of minimum inhibitory concentration(MIC) by agar dilution as described in “Methods for DilutionAntimicrobial Susceptiblity Tests for Bacteria That Grow Aerobically”(MFT) published January 1993 by the National Committee for ClinicalLaboratory Standards (NCCLS), 771 East Lancaster Avenue, Villanova, Pa,19084, USA. The activity of selected compounds of the present inventionagainst Staphylococcus aureus and Streptococcus pneumoniae are shown inTable 2. TABLE 2 Activity of the N-oxides against S. Aureus and S.Pneumoniae. MIC (μg/mL) MIC (μg/mL) Example S. Aureus S. PneumoniaeNumber UC ® 9213 UC ® 9912 1 2 0.5 2 4 1 3 4 1 4 2 0.5 5 4 0.5 6 2 0.25

[0254] As such, the compounds of the present invention are useful fortreating microbial infections in humans or other warm-blooded animals byadministering to a patient in need thereof an effective amount of acompound of Formula I. The compound is administered in a pharmaceuticalcomposition orally, parenterally (such as subcutaneously orintravenously), or topically. Preferably the compound is administered inan amount of from about 0.1 to about 100 mg/kg of body weight/day, morepreferably, from about 3.0 to about 50 mg/kg of body weight/day.

[0255] The following compounds of the present invention (withcross-references to the formulas in the charts below) are preferred:

[0256] X-A R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-(1,1-dioxothiazolidin-3-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide

[0257] X-B R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-(3-oxazolidinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide N-oxide.

[0258] XI-A R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-(1,1-dioxothiomoroholin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide

[0259] XI-C R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-thia-2,2-dioxo-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0260] XII-A R¹═COCH₃, X¹═F, X²═F:(S)-N-[[3-[3,5-difluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide.

[0261] XII-A R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide.

[0262] XII-A R¹═COCH₂O H, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]hydroxyacetamideN-oxide.

[0263] XII-A R¹═CHO, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]formamideN-oxide.

[0264] XII-A R¹═CO₂CH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]methylcarbamateN-oxide.

[0265] XII-A R¹═COCH₂Cl₂, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]dichloroacetamideN-oxide.

[0266] XII-B R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0267] XIII-C R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-(3-oxo-1-azetidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0268] XIII-H R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-(3-methoxy-3-methyl-1-azetidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0269] XIII-K R¹═COCH₃, X¹═F, X²═H, R³═CH₃:(S)-N-[[3-[3-fluoro-4-[3-[(methoxycarbonyl)amino]-1-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0270] XIII-J R¹═COCH₃, X¹═F, X²═H, R²═H:(S)-N-[[3-[3-fluoro-4-[3-[(hydroxyacetyl)amino]-1-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide.

[0271] XIV-E R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-Fluoro-4-(3-hydroxypyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0272] XIV-J R¹═COCH₃, X¹═F, X²═H, R²═H, R⁵═CH₃:(S)-N-[[3-[3-Fluoro-4-(cis-3-(hydroxyacetylamino)-4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0273] XIV-K R¹═COCH₃, X¹═F, X²═H, R³═CH₃, R⁵═CH₃:(S)-N-[[3-[3-Fluoro-4-(trans-3-(methoxycarbonylamino)-4-methylpyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0274] XV-B R¹═COCH₃, X¹═F, X²═H:(S)-N-[3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl]-acetamideN-oxide.

[0275] XV-D R¹═COCH₃, X¹═F, X²═H: (S)-N-[3-[3-fluoro-4-(2-hydroxymethyl-1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl]-acetamideN-oxide.

[0276] XV-M R¹═COCH₃, X¹═F, X²═H:(S)-1-[4-[5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl]-piperidine-4-carboxylic acid ethyl esterN-oxide.

[0277] XV-N R¹═COCH₃, X¹═F, X²═H:(S)-N-[3-[3-fluoro-4-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl]-acetamide N-oxide.

[0278] XVI-C R¹═COCH₃, X¹═F, X²═H:(S)-N-[3-[3-fluoro-4-(4-oxoazepin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl]-acetamideN-oxide.

[0279] XVII-B R¹═COCH₃, X¹═H, X²═H, R³═CH₃:(S)-4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)phenyl)-1-piperazinecarboxylicacid, methyl ester N-oxide.

[0280] XVII-B R¹═COCH₃, X¹═F, X²═H, R³═CH₂CH₃:(S)-4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinecarboxylicacid, ethyl ester N-oxide.

[0281] XVIII-A R¹═COCH₃, X¹═F, X²═H, R²═H:(S)-N-[[3-[3-fluoro-4-[cis-3-(hydroxyacetyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0282] XVIII-C R¹═COCH₃, X¹═F, X²═H, R⁴═cyclopropyl:(S)-N-[[3-[3-fluoro-4-[cis-3-[(cyclopropyl)carbonyl]-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.

[0283] XVIII-D R¹═COCH₃, X¹═F, X²═H, R⁹═CH₃:(S)-N-[[3-[3-fluoro-4-[cis-3-(methylsulfonyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide.

[0284] XVII-A R¹═COCH₃, R²═H, X¹═X²═F:(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide.

[0285] XVII-A R¹═COCH₃, R²═H, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide.

[0286] XVII-B R¹═COCH₃, R³═CH₃, X¹═X²═F:(S)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinecarboxylicacid, methyl ester N-oxide.

[0287] XVII-B R¹═COCH₃, R³═CH₃, X¹═F, X²═H:(S)-4-[4-[5-[(acetylamino)-methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinecarboxylicacid, methyl ester N-oxide.

[0288] The following compounds of the present invention (with crossreferences to the formulas in the charts below) are most preferred:

[0289] XII-A R¹═COCH₃, X¹═X²═F:(S)-N-[[3-[3,5-difluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide;

[0290] XII-A R¹═COCH₃, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide;

[0291] XVII-A R¹═COCH₃, R²═H, X¹═X²═F:(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide;

[0292] XVII-A R¹═COCH₃, R²═H, X¹═F, X²═H:(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide;

[0293] XVII-B R¹═COCH₃, R³═CH₃, X¹═X²═F:(S)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinecarboxylicacid, methyl ester N-oxide;

[0294] XVII-B R¹═COCH₃, R³═CH₃, X¹═F, X²═H:(S)-4-[4-[5-[(acetylamino)-methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinecarboxylicacid, methyl ester N-oxide.

DESCRIPTION OF PREFERRED EMBODIMENTS EXAMPLE 1(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide

[0295]

[0296](S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide(VIII-A, R¹═COCH₃, R²═H, X¹═F, X²═H) (11.8 g) is dissolved in 200 mL ofmethanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure,18.5 g) is added and the resulting suspension is stirred at 25° C. fortwo hours. The reaction is filtered and the filtrate is concentrated toafford a white solid. This solid is chromatographed on silica gel using20% methanol in chloroform as eluent to afford the N-oxide.Lyophilization of this material affords the purified product as ahydrate (9.5 g).

[0297] Physical characteristics are as follows:

[0298] Mp 158-160° C.;

[0299] IR (mull) 3276, 3071, 1754, 1658, 1622, 1502, 1444, 1410, 1286,1255, 1224, 1204, 1135, 1095, 752 cm⁻¹;

[0300] MS (FAB) m/z 411, 565, 412, 411, 396, 395, 394, 393; 392, 335,56.

EXAMPLE 2 S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5zolidinyl]methyl]acetamide N-oxide

[0301]

[0302](S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (III-A, R¹═COCH₃, X¹═F, X²═H) (12.5 g) is suspended in 200 mLof methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80%pure, 11.5 g) is added and the resulting suspension is stirred at 25° C.for two hours. The reaction mixture is filtered and the filtrate isconcentrated to afford a light-yellow solid. This material ischromatographed on silica gel using 10% methanol (saturated withammonia) in chloroform as eluent to afford 8.75 g of the N-oxide.

[0303] Physical characteristics are as follows:

[0304] Mp 202-204° C.;

[0305] IR (mull) 1747, 1669, 1620, 1556, 1508, 1495, 1445, 1413, 1341,1295, 1269, 1232, 1204, 1124, 755 cm⁻¹;

[0306] MS (FAB) m/z 354, 708, 707, 355, 354, 339, 338, 337, 336, 86, 56.

[0307] Anal. Found: C, 53.99; H, 5.70; N, 11.76.

EXAMPLE 3(S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide

[0308]

[0309] Pertrifluoroacetic acid is prepared in situ by the addition of30% H₂O₂ solution (0.15 mL) to trifluoroacetic anhydride (0.45 ML) in 5mL of methylene chloride at 0° C. This solution is stirred at 0° C. forten minutes, at 25° C. for 30 minutes and then cooled back to 0° C.(S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide(VIII-G, R¹═COCH₃, R⁹═CH₃, X ¹═F, X²H) (0.207 g) is added and thereaction is stirred at 25° C. for 30 minutes and then concentrated. Theresidue is chromatographed on silica gel using 10% methanol (saturatedwith ammonia) in chloroform as the eluent to afford 0.14 g of theN-oxide as a hydrate.

[0310] Physical characteristics are as follows:

[0311] Mp 168-170° C.;

[0312] IR(mull) 1751, 1668, 1658, 1503, 1443, 1408, 1340, 1328, 1277,1260, 1226, 1157, 1130, 1081,855 cm⁻¹;

[0313] MS (FAB) m/z 431, 862, 861, 432, 431, 416, 415, 414, 413, 335,56.

EXAMPLE 4(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide.

[0314]

[0315](S)-N-[[3-[3,5-Difluoro4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide(VIII-A, R¹═COCH₃, R²═H, X¹═X²═F) (0.13 g) is dissolved in 5 mL ofmethanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure,0.2 g) is added and the resulting suspension is stirred at 25° C. for 72hours. An additional 0.2 g of monoperoxyphthalic acid is added and thereaction is stirred an additional 48 hours. The reaction mixture isfiltered and the filtrate is concentrated to afford a light-yellow oil.This material is chromatographed on silica gel using 20% methanol(saturated with ammonia) in chloroform as eluent to afford 55 mg of theN-oxide.

[0316] Physical characteristics are as follows:

[0317] Mp 100-105° C.;

[0318] IR (mull) 3292, 1757, 1658, 1636, 1584, 1557, 1497, 1413, 1287,1245, 1213, 1098, 1054, 1043, 1020 cm⁻¹;

[0319] MS (FAB) m/z 429 (M+H), 857, 429, 413, 412, 411, 353, 161, 145,73, 56.

EXAMPLE 5(S)-N-[[3-[4-[4-[(cyanomethyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide.

[0320]

[0321](S)-N-[[3-[4-[4-[(cyanomethyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(VIII-G, R¹═COCH₃, R⁹═NCCH₂, X¹═F, X²═H) (0.550 g) is dissolved in 15 mLof methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80%pure, 0.616 g) is added and the reaction is stirred at room temperaturefor 4 hours. The reaction is then filtered and the filtrate isconcentrated to afford an oil. This oil is chromatographed on silica gelusing 10% methanol (saturated with ammonia) in chloroform as eluent toafford 0.42 g of the N-oxide.

[0322] Physical characteristics are as follows:

[0323] Mp 153-156° C.

[0324] IR (mull) 1748, 1656, 1625, 1503, 1443, 1406, 1357, 1342, 1257,1224, 1161, 1148, 1137, 931, 756 cm⁻¹;

[0325] MS (FAB) m/z 456 (M+H), 457, 456, 441, 440, 439, 438, 336, 335,91, 56.

EXAMPLE 6(S)-N-[[3-[4-[4-[(2-cyanophenyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide N-oxide.

[0326]

[0327](S)-N-[[3-[4-[4-[(2-cyanophenyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(VIII-G, R¹═COCH₃, R⁹═2-cyanophenyl, X¹═F, X²═H) (0.5 g) is suspended in10 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate(80% pure, 0.616 g) is added and the reaction mixture is stirred at roomtemperature for 2 hours. The reaction is concentrated and the resultingoil is chromatographed on silica gel using 7% methanol (saturated withammonia) in chloroform as eluent to afford 0.33 g of the N-oxide.

[0328] Physical characteristics are as follows:

[0329] Mp 190-192° C.

[0330] IR (mull) 1756, 1678, 1661, 1620, 1500, 1486, 1408, 1280, 1256,1222, 1181, 1168, 1129, 1082,924 cm⁻¹;

[0331] MS (FAB) m/z 518 (M+H), 520,519, 518, 503,502, 501, 500, 336,335,56.

EXAMPLE 7 Reduction of the N-oxide of Example 2 in vivo FollowingIntravenous and Oral Administration to Rats.

[0332] The rate and extent of reduction of the N-oxide of Example 2 wasinvestigated in vivo using the following procedures: Six maleSprague-Dawley rats are used for this study. Three rats are given asingle intravenous 10 mg/kg dose of the N-oxide and three rats are givena single oral 25 mg/kg dose of the N-oxide. Blood is collected pre-doseand up to 24 h post dose. The plasma is analyzed for the N-oxide and theparent amine by LC-MS.

[0333] Results:

[0334] Only traces of the N-oxide were found in plasma in the first timepoint immediately post intravenous injection. The parent amine wasdetected in plasma up to 10 h post dosing. The lower limit ofquantitation for the assay was 0.01 μg/mL. Because the N-oxide wasreduced to the parent amine so rapidly, pharmacokinetic parameters weremeasured for the parent amine rather than for the N-oxide.

[0335] After both intravenous and oral dosing of the N-oxide, the Cmax,Tmax and AUC values for the parent amine were very similar to thosefound when the parent amine compound was administered directly to ratsusing the same doses and protocol. The relative bioavailability of theparent amine from the orally administered N-oxide was approximately 100%when compared to orally administered parent amine. The rapid andessentially quantitative conversion of the N-oxide to the parent aminein vivo demonstrates that the N-oxide is a suitable pro-drug for theparent amine.

Chart I—Thiazolidines

[0336]

[0337] wherein Q² is

[0338] wherein X¹ and X² are independently

[0339] —H,

[0340] —F, or

[0341] —Cl;

[0342] wherein R¹ is

[0343] —CHO,

[0344] —COCH₃,

[0345] —COCHCl₂,

[0346] —COCHF₂,

[0347] —CO₂CH₃,

[0348] —SO₂CH₃, or

[0349] —COCH₂OH.

Chart II—Thiomorpholines—Bridged Thiomorpholines

[0350]

[0351] wherein Q² is

[0352] wherin X¹ and X² are independently

[0353] —H,

[0354] —F, or

[0355] —Cl;

[0356] wherein R¹ is

[0357] —CHO,

[0358] —COCH₃,

[0359] —COCHCl₂,

[0360] —COCHF₂,

[0361] —CO₂CH₃,

[0362] —SO₂CH₃, or

[0363] —COCH₂OH.

Chart III—Morpholines—Bridged Morpholines

[0364]

[0365] wherein Q² is

[0366] wherein X¹ and X² are independently

[0367] —H,

[0368] —F, or

[0369] —Cl;

[0370] wherein R¹ is

[0371] —CHO,

[0372] —COCH₃,

[0373] —COCHCl₂,

[0374] —COCHF₂,

[0375] —CO₂CH₃,

[0376] —SO₂CH₃, or

[0377] —COCH₂OH.

Chart IV—Azetidines

[0378]

[0379] wherein Q² is

Chart IV—Azetidines (Continued)

[0380] wherein X¹ and X² are independently

[0381] —H,

[0382] —F, or

[0383] —Cl;

[0384] wherein R¹ is

[0385] —CHO,

[0386] —COCH₃,

[0387] —COCHCl₂,

[0388] —COCHF₂,

[0389] —CO₂CH₃,

[0390] —SO₂CH₃, or

[0391] —COCH₂O H;

[0392] wherein R² is

[0393] —H,

[0394] —CH₃,

[0395] —CH₂Ph, or

[0396] —COCH₃;

[0397] wherein R³ is

[0398] —CH₃,

[0399] —CH₂CH₃,

[0400] —CH₂CH₂CH₃, or

[0401] -phenyl;

[0402] wherein R⁴ is

[0403] —H,

[0404] —CH₃,

[0405] —CH₂CH₃,

[0406] —CH₂CH₂CH₃,

[0407] —CH₂CH₂CH₂CH₃,

Chart IV—Azetidines (Continued)

[0408] -phenyl,

[0409] —CH₂Cl,

[0410] —CHCl₂,

[0411] CH₂F,

[0412] —CHF₂,

[0413] -substituted aryl,

[0414] —CH₂-(aryl), or

[0415] -cycloalkyl (rings of 3-6 carbons).

Chart V—Pyrrolidines

[0416]

[0417] wherein Q² is

Chart V—Pyrrolidines (Continued)

[0418] wherein X ¹ and X² are independently

[0419] —H,

[0420] —F, or

[0421] —Cl;

[0422] wherein R¹ is

[0423] —CHO,

[0424] —COCH₃,

[0425] —COCHCl₂,

[0426] —COCHF₂,

[0427] —CO₂CH₃,

[0428] —SO₂CH₃, or

[0429] —COCH₂OH;

[0430] wherein R² is

[0431] —H,

[0432] —CH₃,

[0433] —CH₂Ph, or

[0434] —COCH₃;

[0435] wherein R³ is

[0436] —CH₃,

[0437] —CH₂CH₃,

[0438] —CH₂CH₂CH₃, or

[0439] -phenyl;

[0440] wherein R⁴ is

[0441] —H,

[0442] —CH₃,

[0443] —CH₂CH₃,

[0444] —CH₂CH₂CH₃,

[0445] —CH₂CH₂CH₂CH₃,

Chart V—Pyrrolidines (Continued)

[0446] -phenyl,

[0447] —CH₂Cl,

[0448] —CHCl₂,

[0449] CH₂F,

[0450] —CHF₂,

[0451] -substituted aryl,

[0452] —CH₂-(aryl), or

[0453] -cycloalkyl (rings of 3-6 carbons);

[0454] wherein R⁵ is

[0455] —H,

[0456] —CH₃,

[0457] —CH₂CH₃, or

[0458] —CH₂CH₂CH₃.

Chart VI—Piperidines

[0459]

[0460] wherein Q² is

Chart VI—Piperidines (Continued)

[0461] wherein X¹ and X² are independently

[0462] —H,

[0463] —F, or

[0464] —Cl;

[0465] wherein R¹ is

[0466] —CHO,

[0467] —COCH₃,

[0468] —COCHCl₂,

[0469] —COCHF₂,

[0470] —CO₂CH₃,

[0471] —SO₂CH₃, or

[0472] COCH₂O H;

[0473] wherein R² is

[0474] —H,

[0475] —CH₃,

[0476] —CH₂Ph, or

[0477] —COCH₃;

[0478] wherein R³ is

[0479] —CH₃,

[0480] —CH₂CH₃,

[0481] —CH₂CH₂CH₃, or

[0482] -phenyl;

[0483] wherein R⁴ is

[0484] —H,

[0485] —CH₃,

[0486] —CH₂CH₃,

[0487] —CH₂CH₂CH₃,

[0488] —CH₂CH₂CH₂CH₃,

Chart VI—Piperidines (continued)

[0489] -phenyl,

[0490] —CH₂Cl,

[0491] —CHCl₂,

[0492] CH₂F,

[0493] —CHF₂,

[0494] -substituted aryl,

[0495] —CH₂-(aryl), or

[0496] -cycloalkyl (rings of 3-6 carbons).

[0497] Chart VII—Azepines

[0498] wherein Q² is

Chart VII—Azepines (Continued)

[0499] wherein X¹ and X² are independently

[0500] —H,

[0501] —F, or

[0502] —Cl;

[0503] wherein R¹ is

[0504] —CHO,

[0505] —COCH₃,

[0506] —COCHCl₂,

[0507] —COCHF₂,

[0508] —CO₂CH₃,

[0509] —SO₂CH₃, or

[0510] —COCH₂OH;

[0511] wherein R² is

[0512] —H,

[0513] —CH₃,

[0514] —CH₂Ph, or

[0515] —COCH₃;

[0516] wherein R³ is

[0517] —CH₃,

[0518] —CH₂CH₃,

[0519] —CH₂CH₂CH₃, or

[0520] -phenyl;

[0521] wherein R⁴ is

[0522] —H,

[0523] —CH₃,

[0524] —CH₂CH₃,

[0525] —CH₂CH₂CH₃,

[0526] —CH₂CH₂CH₂CH₃,

Chart VII—Azepines (Continued)

[0527] -phenyl,

[0528] —CH₂Cl,

[0529] —CHCl₂,

[0530] CH₂F,

[0531] —CHF₂,

[0532] -substituted aryl,

[0533] —CH₂-(aryl), or

[0534] -cycloalkyl (rings of 3-6 carbons).

Chart VIII—Piperazines

[0535]

[0536] wherein Q² is

[0537] —H,

[0538] —F, or

[0539] —Cl;

[0540] wherein R¹ is

[0541] —CHO,

[0542] —COCH₃,

[0543] —COCHCl₂,

Chart VIII—Piperazines (Continued)

[0544] —COCHF₂,

[0545] —CO₂CH₃,

[0546] —SO₂CH₃, or

[0547] —COCH₂O H;

[0548] wherein R² is

[0549] —H,

[0550] —CH₃,

[0551] —CH₂Ph, or

[0552] —COCH₃;

[0553] wherein R³ is

[0554] —CH₃,

[0555] —CH₂CH₃,

[0556] —CH₂CH₂CH₃, or

[0557] -phenyl;

[0558] wherein R⁴ is

[0559] —H,

[0560] —CH₃,

[0561] —CH₂CH₃,

[0562] —CH₂CH₂CH₃,

[0563] —CH₂CH₂CH₂CH₃,

[0564] -phenyl,

[0565] —CH₂Cl,

[0566] —CHCl₂,

[0567] CH₂F,

[0568] —CHF₂,

[0569] -substituted aryl,

[0570] —CH₂-(aryl), or

[0571] -cycloalkyl (rings of 3-6 carbons);

Chart VIII—Piperazines (Continued)

[0572] wherein R⁹ is

[0573] —CH₃,

[0574] —CH₂Cl,

[0575] —CH₂CH═CH₂,

[0576] substituted aryl, or

[0577] —CH₂CN;

[0578] wherein R¹⁰ and R¹¹ are independently

[0579] —H,

[0580] —CH₃, or

[0581] -together form a cyclopropyl ring;

[0582] wherein R¹² is

[0583] —CH₂Ph, or

[0584] -substituted aryl.

Chart IX—Pyrrolopyrrolidines

[0585]

[0586] wherein Q² is

[0587] wherein X¹ and X² are independently

[0588] —H,

[0589] —F, or

[0590] —Cl;

Chart IX—Pyrrolopyrrolidines (Continued)

[0591] wherein R¹ is

[0592] —CHO,

[0593] —COCH₃,

[0594] —COCHCl₂,

[0595] —COCHF₂,

[0596] —CO₂CH₃,

[0597] —SO₂CH₃, or

[0598] —COCH₂O H;

[0599] wherein R² is

[0600] —H,

[0601] —CH₃,

[0602] —CH₂Ph, or

[0603] —COCH₃;

[0604] wherein R³ is

[0605] —CH₃,

[0606] —CH₂CH₃,

[0607] —CH₂CH₂CH₃, or

[0608] -phenyl;

[0609] wherein R⁴ is

[0610] —H,

[0611] —CH₃,

[0612] —CH₂CH₃,

[0613] —CH₂CH₂CH₃,

[0614] —CH₂CH₂CH₂CH₃,

[0615] -phenyl,

[0616] —CH₂Cl,

[0617] —CHCl₂,

[0618] —CH₂F,

Chart IX—Pyrrolopyrrolidines (Continued)

[0619] —CHF₂,

[0620] -substituted aryl,

[0621] —CH₂-(aryl), or

[0622] -cycloalkyl (rings of 3-6 carbons);

[0623] wherein R⁹ is

[0624] —CH₃,

[0625] —CH₂Cl,

[0626] —CH₂CH═CH₂,

[0627] substituted aryl, or

[0628] —CH₂CN;

[0629] wherein R¹⁰ and R¹¹ are independently

[0630] —H,

[0631] —CH₃, or

[0632] -together form a cyclopropyl ring;

[0633] wherein R¹² is

[0634] —CH₂Ph, or

[0635] -substituted aryl.

Chart X—Thiazolidines

[0636]

[0637] wherein Q¹ is

[0638] wherein X¹ and X² are independently

[0639] —H,

[0640] —F, or

[0641] —Cl;

[0642] wherein R¹ is

[0643] —CHO,

[0644] —COCH₃,

[0645] —COCHCl₂,

[0646] —COCHF₂,

[0647] —CO₂CH₃,

[0648] —SO₂CH₃, or

[0649] —COCH₂OH.

Chart XI—Thiomorpholines—Bridged Thiomorpholines

[0650]

[0651] wherein Q¹ is

[0652] wherein ¹ and X² are independently

[0653] —H,

[0654] —F, or

[0655] —Cl;

[0656] wherein R¹ is

[0657] —CHO,

[0658] —COCH₃,

[0659] —COCHCl₂,

[0660] —COCHF₂,

[0661] —CO₂CH₃,

[0662] —SO₂CH₃, or

[0663] —COCH₂OH.

Chart XII—Morpholines—Bridged Morpholines

[0664]

[0665] wherein Q¹ is

[0666] wherein X¹ and X² are independently

[0667] —H,

[0668] —F, or

[0669] —Cl;

[0670] wherein R¹ is

[0671] —CHO,

[0672] —COCH₃,

[0673] —COCHCl₂,

[0674] —COCHF₂,

[0675] —CO₂CH₃,

[0676] —SO₂CH₃, or

[0677] —COCH₂O H.

Chart XIII—Azetidines

[0678]

[0679] wherein Q¹ is

Chart XIII—Azetidines (Continued)

[0680] wherein X¹ and X² are independently

[0681] —H,

[0682] —F, or

[0683] —Cl;

[0684] wherein R¹ is

[0685] —CHO,

[0686] —COCH₃,

[0687] —COCHCl₂,

[0688] —COCHF₂,

[0689] —CO₂CH₃,

[0690] —SO₂CH₃, or

[0691] —COCH₂O H;

[0692] wherein R² is

[0693] —H,

[0694] —CH₃,

[0695] —CH₂Ph, or

[0696] —COCH₃;

[0697] wherein R³ is

[0698] —CH₃,

[0699] —CH₂CH₃,

[0700] —CH₂CH₂CH₃, or

[0701] -phenyl;

[0702] wherein R⁴ is

[0703] —H,

[0704] —CH₃,

[0705] —CH₂CH₃,

[0706] —CH₂CH₂CH₃,

[0707] —CH₂CH₂CH₂CH₃,

Chart XIII—Azetidines (Continued)

[0708] -phenyl,

[0709] —CH₂Cl,

[0710] —CHCl₂,

[0711] CH₂F,

[0712] —CHF₂,

[0713] -substituted aryl,

[0714] —CH₂-(aryl), or

[0715] -cycloalkyl (rings of 3-6 carbons).

Chart XIV—Pyrrolidines

[0716]

[0717] wherein Q¹ is

Chart XIV—Pyrrolidines (Continued)

[0718] wherein X¹ and X² are independently

[0719] —H,

[0720] —F, or

[0721] —Cl;

[0722] wherein R¹ is

[0723] —CHO,

[0724] —COCH₃,

[0725] —COCHCl₂,

[0726] —COCHF₂,

[0727] —CO₂CH₃,

[0728] —SO₂CH₃, or

[0729] —COCH₂OH;

[0730] wherein R² is

[0731] —H,

[0732] —CH₃,

[0733] —CH₂Ph, or

[0734] —COCH₃;

[0735] wherein R³ is

[0736] —CH₃,

[0737] —CH₂CH₃,

[0738] —CH₂CH₂CH₃, or

[0739] -phenyl;

[0740] wherein R⁴ is

[0741] —H,

[0742] —CH₃,

[0743] —CH₂CH₃,

[0744] —CH₂CH₂CH₃,

[0745] —CH₂CH₂CH₂CH₃,

Chart XIV—Pyrrolidines (Continued)

[0746] -phenyl,

[0747] —CH₂Cl,

[0748] —CHCl₂,

[0749] CH₂F,

[0750] —CHF₂,

[0751] -substituted aryl,

[0752] —CH₂-(aryl), or

[0753] -cycloalkyl (rings of 3-6 carbons);

[0754] wherein R⁵ is

[0755] —H,

[0756] —CH₃,

[0757] —CH₂CH₃, or

[0758] —CH₂CH₂CH₃.

Chart XV—Piperidines

[0759]

[0760] wherein Q¹ is

Chart XV—Piperidines (Continued)

[0761] wherein X¹ and X² are independently

[0762] —H,

[0763] —F, or

[0764] —Cl;

[0765] wherein R¹ is

[0766] —CHO,

[0767] —COCH₃,

[0768] —COCHCl₂,

[0769] —COCHF₂,

[0770] —CO₂CH₃,

[0771] —SO₂CH₃, or

[0772] COCH₂OH;

[0773] wherein R² is

[0774] —H,

[0775] —CH₃,

[0776] —CH₂Ph, or

[0777] —COCH₃;

[0778] wherein R³ is

[0779] —CH₃,

[0780] —CH₂CH₃,

[0781] —CH₂CH₂CH₃, or

[0782] -phenyl;

[0783] wherein R⁴ is

[0784] —H,

[0785] —CH₃,

[0786] —CH₂CH₃,

[0787] —CH₂CH₂CH₃,

[0788] —CH₂CH₂CH₂CH₃,

Chart XV—Piperidines (continued)

[0789] -phenyl,

[0790] —CH₂CI,

[0791] —CHCl₂,

[0792] CH₂F,

[0793] —CHF₂,

[0794] -substituted aryl,

[0795] —CH2-(aryl), or

[0796] -cycloalkyl (rings of 3-6 carbons).

Chart XVI—Azepines

[0797]

[0798] wherein Q¹ is

Chart XVI—Azepines (Continued)

[0799] wherein X¹ and X² are independently

[0800] —H,

[0801] —F, or

[0802] —Cl;

[0803] wherein R¹ is

[0804] —CHO,

[0805] —COCH₃,

[0806] —COCHCl₂,

[0807] —COCHF₂,

[0808] —CO₂CH₃,

[0809] —SO₂CH₃, or

[0810] —COCH₂O H;

[0811] wherein R² is

[0812] —H,

[0813] —CH₃,

[0814] —CH₂Ph, or

[0815] —COCH₃;

[0816] wherein R³ is

[0817] —CH₃,

[0818] —CH₂CH₃,

[0819] —CH₂CH₂CH₃, or

[0820] -phenyl;

[0821] wherein R⁴ is

[0822] —H,

[0823] —CH₃,

[0824] —CH₂CH₃,

[0825] —CH₂CH₂CH₃,

[0826] —CH₂CH₂CH₂CH₃,

Chart XVI—Azepines (Continued)

[0827] -phenyl,

[0828] —CH₂Cl,

[0829] —CHCl₂,

[0830] CH₂F,

[0831] —CHF₂,

[0832] -substituted aryl,

[0833] —CH₂-(aryl), or

[0834] -cycloalkyl (rings of 3-6 carbons).

Chart XVII—Piperazines

[0835]

[0836] wherein Q¹ is

Chart XVIII—Piperazines (Continued)

[0837] wherein X¹ and X² are independently

[0838] —H,

[0839] —F, or

[0840] —Cl;

[0841] wherein R¹ is

[0842] —CHO,

[0843] —COCH₃,

[0844] —COCHCl₂,

[0845] —COCHF₂,

[0846] —CO₂CH₃,

[0847] —SO₂CH₃, or

[0848] —COCH₂O H;

[0849] wherein R² is

[0850] —H,

[0851] —CH₃,

[0852] —CH₂Ph, or

[0853] —COCH₃;

[0854] wherein R³ is

[0855] —CH₃,

[0856] —CH₂CH₃,

[0857] —CH₂CH₂CH₃, or

[0858] -phenyl;

[0859] wherein R⁴ is

[0860] —H,

[0861] —CH₃,

[0862] —CH₂CH₃,

[0863] —CH₂CH₂CH₃,

[0864] —CH₂CH₂CH₂CH₃,

Chart XVII—Piperazines (Continued)

[0865] -phenyl,

[0866] —CH₂C1,

[0867] —CHCl₂,

[0868] CH₂F,

[0869] —CHF₂,

[0870] -substituted aryl,

[0871] —CH₂-(aryl), or

[0872] -cycloalkyl (rings of 3-6 carbons);

[0873] wherein R⁹ is

[0874] —CH₃,

[0875] —CH₂Cl,

[0876] —CH₂CH═CH₂,

[0877] substituted aryl, or

[0878] —CH₂CN;

[0879] wherein R¹⁰ and R¹¹ are independently

[0880] —H,

[0881] —CH₃, or

[0882] -together form a cyclopropyl ring;

[0883] wherein R¹² is

[0884] —CH₂Ph, or

[0885] -substituted aryl.

Chart XVIII—Pyrrolopyrrolidines

[0886]

[0887] wherein Q¹ is

[0888] wherein X¹ and X² are independently

[0889] —H,

[0890] —F, or

[0891] —Cl;

Chart XVIII—Pyrrolopyrrolidines (Continued)

[0892] wherein R¹ is

[0893] —CHO,

[0894] —COCH₃,

[0895] —COCHCl₂,

[0896] —COCHF₂,

[0897] —CO₂CH₃,

[0898] —SO₂CH₃, or

[0899] —COCH₂O H;

[0900] wherein R² is

[0901] —H,

[0902] —CH₃,

[0903] —CH₂Ph, or

[0904] —COCH₃;

[0905] wherein R³ is

[0906] —CH₃,

[0907] —CH₂CH₃,

[0908] —CH₂CH₂CH₃, or

[0909] -phenyl;

[0910] wherein R⁴ is

[0911] —H,

[0912] —CH₃,

[0913] —CH₂CH₃,

[0914] —CH₂CH₂CH₃,

[0915] —CH₂CH₂CH₂CH₃,

[0916] -phenyl,

[0917] —CH₂Cl,

[0918] —CHCl₂,

[0919] —CH₂F,

Chart XVIII—Pyrrolopyrrolidines (Continued)

[0920] —CHF₂,

[0921] -substituted aryl,

[0922] —CH₂-(aryl), or

[0923] -cycloalkyl (rings of 3-6 carbons);

[0924] wherein R⁹ is

[0925] —CH₃,

[0926] —CH₂Cl,

[0927] —CH₂CH═CH₂,

[0928] substituted aryl, or

[0929] —CH₂CN;

[0930] wherein R¹⁰ and R¹¹ are independently

[0931] —H,

[0932] —CH3, or

[0933] -together form a cyclopropyl ring;

[0934] wherein R¹² is

[0935] —CH₂Ph, or

[0936] -substituted aryl.

1. A compound of the formula I

wherein X¹ and X² are independently —H, —F, or —Cl; wherein Q¹ is:

wherein Z¹ is a) —CH₂—, or b) —CH(R⁵)—CH₂—; wherein Z² is a) —O₂S—, b)—O—, or c) —N(R⁸)—; wherein Z³ is a) —O₂S—, or b) —O—; wherein A¹ is a)H—, or b) CH₃—; wherein A² is a) H—, b) HO—, C) CH₃CO₂—, d) CH₃—, e)CH₃O—, f) R²O—CH₂—C(O)—NH— g) R³O—C(O)—NH—, h) R⁴—C(O)—NH—, i)(C₁-C₂)alkyl-O—C(O)—, or j) HO—CH₂—; or A¹ and A² taken together are: a)

or b) O═ wherein R¹ is a) —CHO, b) —COCH₃, c) —COCHCl₂, d) —COCHF₂, e)—CO₂CH₃, f) —SO₂CH₃, or g) —COCH₂OH; wherein R² is a) H—, b) CH₃—, c)phenyl-CH₂—, or d) CH₃C(O)—; wherein R³ is a) (C₁-C₃)alkyl-, or b)phenyl-; wherein R⁴ is a) H—, b) (C₁-C₄)alkyl, c) aryl-(CH₂)_(p), d)ClH₂C—, e) Cl₂HC—, f) FH₂C—, g) F₂HC—, or h) (C₃-C₆)cycloalkyl; whereinR⁵ is a) H—, or b) (C₁-C₃)alkyl; wherein R⁶ is a) H—, or b) HOH₂C—;wherein R⁷ is a) H—, or b) H₃C—; wherein R⁸ is a) R²O—C(R₁₀)(R₁₁)—C(O)—,b) R³O—C(O)—, c) R⁴—C(O)—,

f) H₃C—C(O)—(CH₂)₂—C(O)—, g) R⁹—SO₂—,

i) R¹²—NH—C(O)—; wherein R⁹ is a) —CH₃, b) —CH₂Cl c) —CH₂CH═CH₂, d)aryl, or e) —CH₂CN; wherein R¹⁰ and R¹¹ are independently a) H—, b)CH₃—; or R¹⁰ and R¹¹ taken together are —CH₂—CH₂—; wherein R¹² is—(CH₂)_(p)-aryl; wherein R¹³ is a) R²O—C(R₁₀)(R₁₁)—C(O)—, b) R³O—C(O)—,c) R⁴—C(O)—, d) R⁹—SO₂—, or e) R¹²—NH—C(O)—; wherein m is zero (0) orone (1); wherein n is one (1) to three (3), inclusive; wherein p is zero(0) or one (1); wherein aryl is phenyl substituted with zero (0) or one(1) of the following: a) —F, b) —Cl, c) —OCH₃, d) —OH, e) —NH₂, f)—(C₁-C₄)alkyl, g) —O—C(O)—OCH₃, h) —NO₂, or i) —CN; with the followingprovisos: 1) in the moiety of formula II, Z¹ is —CH(R⁵)—CH₂— wherein R⁵is (C₁-C₃)alkyl, only when n is one (1), A¹ is H and A² isR²O—CH₂—C(O)—NH—, R³—C(O)—NH—, or R⁴—C(O)—NH—; and 2) in the moiety offormula II, when Z¹ is —CH₂—, n is one (1).
 2. The compound of claim 1wherein Q¹ is the moiety of formula II.
 3. The compound of claim 1wherein Q¹ is the moiety of formula III.
 4. The compound of claim 1wherein Q¹ is the moiety of formula IV.
 5. The compound of claim 1wherein Q¹ is the moiety of formula V.
 6. The compound of claim 1wherein one of X¹ and X² is —H and the other is —F or wherein X¹ is —Fand X² is —F.
 7. The compound of claim 1 wherein R¹ is acetyl.
 8. Thecompound of claim 1 selected from the group consisting of:(S)-N-[[3-[3-fluoro-4-(1,1-dioxothiazolidin-3-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3-fluoro-4-(3-oxazolidinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide N-oxide;(S)-N-[[3-[3-fluoro4-(1,1-dioxothiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-thia-2,2-dioxo-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3,5-difluoro4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide;(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide N-oxide;(S)-N-[[3-[3-fluoro4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-hydroxyacetamideN-oxide;(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-formamideN-oxide;(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-methylcarbamateN-oxide;(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-dichloroacetamideN-oxide; (S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide;(S)-N-[[3-[3-fluoro-4-(3-oxo-1-azetidinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide;(S)-N-[[3-[3-fluoro-4-(3-methoxy-3-methyl-1-azetidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide;(S)-N-[[3-[3-fluoro-4-[3-[(methoxycarbonyl)amino]-1-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide N-oxide;(S)-N-[[3-[3-fluoro-4-[3-[(hydroxyacetyl)amino]-1-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3-Fluoro-4-(3-hydroxypyrrolidinyl)phenyll-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide;(S)-N-[[3-[3-Fluoro-4-(cis-3-(hydoxyacetylamino)-4-methylpyrrolidinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide;(S)-N-[[3-[3-Fluoro-4-(trans-3-(methoxycarbonylamino)-4-methyl-pyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide; (S)-N-[3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin -5-ylmethyl]-acetamideN-oxide;(S)-N-[3-[3-fluoro-4-(2-hydroxymethyl-1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl] -2-oxo-oxazolidin-5-ylmethyl]-acetamide N-oxide;(S)-1-[4-[5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl]-piperidine-4-carboxylicacid ethyl ester N-oxide;(S)-N-[3-[3-fluoro-4-(4-hydroxymethylpiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl]-acetamide N-oxide;(S)-N-[3-[3-fluoro-4-(4-oxoazepin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl]-acetamideN-oxide;(S)-4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)phenyl)-1-piperazinecarboxylicacid, methyl ester N-oxide;(S)-4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinecarboxylicacid, ethyl ester N-oxide;(S)-N-[[3-[3-fluoro-4-[cis-3-(hydroxyacetyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3-fluoro-4-[cis-3-[(cyclopropyl)carbonyl]-3,7-diazabicyclo[3.3.0]-octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3-fluoro-4-[cis-3-(methylsulfonyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide N-oxide;(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyllphenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide;(S)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinecarboxylicacid, methyl ester N-oxide; and(S)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinecarboxylicacid, methyl ester N-oxide.
 9. The compound of claim 8 selected from thegroup consisting of:(S)-N-[[3-[3,5-difluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide N-oxide;(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide N-oxide;(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperazinecarboxylicacid, methyl ester N-oxide; and(S)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinecarboxylicacid, methyl ester N-oxide.
 10. The compound of claim 1 selected fromthe group consisting of:(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide;(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide;(S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide;(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamideN-oxide; 5(S)-N-[[3-[4-[4-[(cyanomethyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide; and(S)-N-[[3-[4-[4-[(2-cyanophenyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamideN-oxide.